HRT(Hormone Replacement Therapy)

and

DRIM(Drugs and Roentgen Induced Menopause)

M. LuertiDipartimento Materno Infantile

U.O. di Ostetricia e Ginecologia - Presidio di Lodi

ASL della Provincia di Lodi - Regione Lombardia - Italia

HRT and DRIM

Notwithstanding increasing epidemiological frequency of DRIM mainly because of diffusion of recent drugs:

• Chemotherapies• GnRH analogues

• Danazol• Gestrinone

knowledge about this topic is rather lacking

FACTORS AFFECTING DRIM

• Disease motivating the induction of menopause

• Ovarian failure inducing agent

• Postmenopausal ageing in relation to the age at which menopause occurs

DISEASES MOTIVATING THE INDUCTION OF MENOPAUSE

Lymphomas Breast cancer

Leukaemia Auto-immune diseases

Soft tissue cancer Endometriosis

Wilms tumor Uterine myomas

Osteosarcoma Persistent menorrhagia

Trophoblastic tumors Cardiovascular diseases

PRIMITIVE DISEASE CAN EXACERBATE SOME SYMPTOMS

Disease Symptoms

Cancer Sexual life deterioration

Anxiety

Endometriosis Depression

Sleeplessness

Cardiovascular diseases Fatigue

Anaemia

Osteoporosis

Dyspareunia

FACTORS AFFECTING PROBABILITY OF OVARIAN FAILURE

•Age of the patient

•Duration of treatment

•Dose

•Fractionation of doses

•Association of agents (polichemotherapy)

FOLLICLE RESERVE IN WOMEN OF DIFFERENT AGES

Age Average n. of primordial Extreme limits

follicles

Birth 480.000 260.000-750.000

15-30 150.000 40.000-300.000

31-40 75.000 15.000-200.000

> 40 8.000 350-25.000

CHEMOTHERAPY AND OVARIAN CYTOTOXICITY

Definite Probable*Chlorambucil *Doxorubicin*Cyclophosphamide *Vinblastine*L-Phenylalanine Mustard *Cytosine Arabinoside*Nitrogen Mustard *Cisplatin*Busulfan *Nitrosureas*Procarbazine *m-AMSA

*Etoposide

Unknown Unlikely*Bleomicin *Methotrexate

*Fluorouracil*Mercaptopurine*Vincristine

OVARIAN FAILURE INDUCING AGENTS

ReversibleHormones

Irreversible

53% irreversible under age 35Chemotherapy 84% between ages 35-44

94% age 45 or older

Reversible (< 250 r/ovary)Radiotherapy

Irreversible (> 250 r/ovary)

OVARIAN FAILURE INDUCING AGENTS CAN EXACERBATE SOME CLIMATERIC SYMPTOMS

Agent Symptoms

FatigueChemotherapy

Anaemia

Hormonal therapyCardiovascular disease

Radiotherapy Osteoporosis

Atrophy and dyspareunia

POSTMENOPAUSAL AGEING

The lower the age of induced

menopause, the stronger the

symptoms and higher the risk of

long-term effects

CONSEQUENCES OF SUDDEN OVARIAN FAILURE

Surgical removal of both ovaries constitutes the better model to represent DRIM and its consequences on symptoms associated

Evident increase of vaginal atrophy

Evident decline of sexual activity

CONSEQUENCES OF SUDDEN OVARIAN FAILURE

The model based on surgical induction of menopause is the most important suitable and shows:

•A higher osteoporotic risk

• A higher cardiovascular risk

• A net increase in the frequency of vaginal atrophy and decline of sexual activity

CLIMATERIC SYNDROME IN DRIM

The climateric syndrome in DRIM is more severe than in natural

postmenopause, mainly due to increased intensity of

psychoemotional complaints (nervousness, depression, insomnia

and fatigue), largely due to the stress involved in DRIM

LONG-TERM EFFECTS IN DRIM

The risk of long-term effects in DRIM is higher than in natural

postmenopause, mainly due to:

•the action of ovarian failure inducing agent

•postmenopausal ageing

HRT and DRIM

HRT should be useful in DRIM even more than in spontaneous menopause

Unfortunately the intensity of the symptoms and consequences of DRIM is

in contrast with the reluctance of the physician to treat patients

RELUCTANCE OF THE PHYSICIAN: WHY?

Is HRT contraindicated in DRIM?because of inducing agent?

because of primitive illness?

HRT and DRIM

There are no contraindications to the use of HRT in DRIM in

relation to ovarian failure inducing agent

HRT IN PATIENTS TREATED FOR BREAST CANCER

It is a general belief that HRT after breast cancer will

increase the risk of developing recurrences, though there are

no clear data available to support this suggestion

RECURRENCES AFTER HRT IN PATIENTS TREATED FOR BREAST CANCER

HRT NON HRT

Eden, 1995 7% 17%

Wren, 1995 9% 17%

DiSaia,1996 14,6% 7,3%

The National Cancer Institute of the United States, in 1996, initiated a randomised, prospective trial of HRT following treatment of breast cancer in

women with Stage 1 and 2 disease.

Inclusion criteria are:

- disease free for 2 years with estrogen receptor negative disease

- 10 years following a breast cancer with estrogen receptor status unknown

RECURRENCES AND SURVIVAL AFTER HRT IN PATIENTS TREATED FOR ENDOMETRIAL CANCER

Recurrences

ERT NON ERT

Chapman, 1996 3,2% 9,8%

Lee, 1990 0% 1,6%

Creasman, 1986 2,1% 14,9%

6 years survival

Creasman, 1986 93% 52%

HRT IN PATIENTS TREATED FOR OVARIAN CANCER

RR IC (95%)

Mortality 0,73 0,44 – 1,20

Recurrences 0,90 0,52 – 1,54

From Eeles, 1991, modified

HRT AND GYNECOLOGICAL CANCERfrom THE CANADIAN CONSENSUS CONFERENCE ON MENOPAUSE AND

OSTEOPOROSIS, 1998

•Breast cancer: HRT may be offered after proper individual counselling

•Endometrial cancer: HRT should not be withheld in treated Stage 1 or 2 Grade 1 or 2

•Ovarian cancer: HRT should not be withheld in these patients, after proper counselling

•Cervical cancer: Several studies support the use of HRT in patients treated for squamous cell carcinoma of the cervix

•Vaginal and vulvar cancers: There is no relevant published information indicating that HRT use has a negative effect on either squamous cell carcinoma of the vagina or the vulva

HRT and OTHER CANCERfrom THE CANADIAN CONSENSUS CONFERENCE ON MENOPAUSE AND

OSTEOPOROSIS, 1998

•Colo-rectal cancer: There are no data showing any change in risk associated with HRT in women who have been treated for colon cancer

•Melanoma: cutaneous non-metastatic melanoma is not a contra-indication to the use of post-menopausal estrogen

•Thyroid cancer: While it is recognized that, in post-menopausal women, well differentiated papillary and follicular carcinomas may be particularly aggressive, there is no evidence

HRT after ENDOMETROSIS INDUCED MENOPAUSEfrom THE CANADIAN CONSENSUS CONFERENCE ON MENOPAUSE AND

OSTEOPOROSIS, 1998

Combined estrogen and progestin replacement therapy in standard doses does not appear to cause regrowth of endometriosis in menopausal women, or in young women receiving estrogen-progestin “addback” therapy following medical oophorectomy with

GnRH analogues.

A small subgroup of women may experience recurrence of pain and other symptoms during unopposed estrogen therapy, particularly if residual disease remains following

definitive surgery.

There are anecdotal reports of endometrial cancer developing in residual endometriosis in women receiving unopposed estrogen following definitive surgery for endometriosis.

This appears to be one of the few indications for progestin therapy following hysterectomy, either as part of a

continuous-combined regimen or as progestin-only therapy.

Available data do not allow a definitive answer to this question.

HRT after FIBROIDS INDUCED MENOPAUSEfrom THE CANADIAN CONSENSUS CONFERENCE ON MENOPAUSE AND

OSTEOPOROSIS, 1998

Uterine fibroids do not constitute a contra-indication

to HRT, but it should be used with caution in women

known to have fibroids.

Although both estrogen and progestins can influence fibroid growth, the doses in conventional HRT regimens are usually not sufficient to cause enlargement of fibroids.

However, rapid growth or abnormal bleeding (from a submucous fibroid) requires investigation and possibly surgical intervention.

HRT and DRIM

HRT DOESN’T APPEAR TO

BE CONTRAINDICATED

AND ADVISABLE IN MOST

CASES OF DRIM

HRT IN PATIENTS TREATED FOR BREAST AND ENDOMETRIAL CANCER

It is recommended the use of

a continuous combined

estro-progestin therapy

COMPLEMENTARY APPROACHES TO DRIM

•Other medicationsClonidineBellergal®Topical estrogensHigh doses progestinsBisphosphonatesSERMs

•Diet and lifestyle

•Phytoestrogens

•Herbal remediesCimicifuga racemosaHypericum perforatumGinkgo bilobaValeriana officinalisEvening Primrose Oil